Acetylenes disubstituted with a heteroaromatic group and a tetralin group and having retinoid like activity

ABSTRACT

Retinoid-like activity is exhibited by compounds of the formula ##STR1## where R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-5; and B is H, --COOH or an ester or amide thereof, --CH 2  OH or an ether or ester derivative thereof, or --CHO or an acetal derivative thereof, or --COR 1  or a ketal derivative thereof where R 1  is --(CH 2 ) m  CH 3  where m is 0-4; or a pharmaceutically acceptable salt thereof.

This patent application is a divisional patent application of U.S. Ser.No. 08/084,843, now U.S. Pat. No. 5,354,776, which was filed 29 Jun.,1993 in the name of Chandraratna which is a division of U.S. Ser. No.07/947,681, now U.S. Pat. No. 5,246,962, which was filed on 21 Sep.,1992 in the name of Chandraratna which us itself a division of U.S. Ser.No. 07/025,434, now U.S. Pat. No. 5,149,705, which was filed on 13 Mar.,1987 in the name of Chandraratna.

BACKGROUND

This invention relates to novel compounds having retinoid-like activity.More specifically, the invention relates to compounds having anethynylheteroaromatic acid portion and a second portion which is atetrahydro naphthalene group. The acid function may also be converted toan alcohol, aldehyde or ketone or derivatives thereof, or may be alkylor H.

RELATED ART

Carboxylic acid derivatives useful for inhibiting the degeneration ofcartilage of the general formula4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X istetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed inEuropean Patent Application 0133795 published Jan. 9, 1985. See alsoEuropean Patent Application 176034A published Apr. 2, 1986 wheretetrahydro naphthalene compounds having an ethynylbenzoic acid group aredisclosed.

SUMMARY OF THE INVENTION

This invention covers compounds of formula I ##STR2## where R ishydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl or pyrazinyl; n is 0-5; and B is H, --COOH or apharmaceutically acceptable salt, ester or amide thereof, --CH₂ OH or anether or ester derivative thereof, or --CHO or an acetal derivativethereof, or --COR₁ or a ketal derivative thereof where R₁ is --(CH₂)_(m)CH₃ where m is 0-4; or a pharmaceutically acceptable salt thereof.

In a second aspect, this invention relates to the use of the compoundsof formula I for treating dermatoses, such as acne, Darier's disease,psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.These compounds are also useful in the treatment of arthritic diseasesand other immunological disorders (e.g., lupus erythematosus), inpromoting wound healing and in treating dry eye syndrome and inreversing the effects of sun damage to the skin.

This invention also relates to a pharmaceutical formulation comprising acompound of formula I in admixture with a pharmaceutically acceptableexcipient, particularly one having anti-psoriatic activity. In anotheraspect, this invention relates to the process for making a compound offormula I which process comprises reacting a compound of formula II witha compound of formula III in the presence of Pd(PQ₃)₄ (Q is phenyl) or asimilar complex ##STR3## where X is a halogen, preferably I; n and A aredefined above; and B is H, or a protected acid, alcohol, aldehyde orketone, giving the corresponding compound of formula I; or

converting an ester to an acid or salt; or

converting an acid of formula I to a salt; or

converting an acid of formula I to an ester; or

converting an acid of formula I to an amide; or

reducing an acid of formula I to an alcohol or aldehyde; or

converting an alcohol of formula I to an ether or ester; or

ozidizing an alcohol of formula I to an aldehyde; or

converting an aldehyde of formula I to an acetal; or

converting a ketone of formula I to a ketal; or

converting an alcohol of formula I to a methyl group.

GENERAL EMBODIMENTS Definitions

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where B is --COOH, this term covers the products derived fromtreatment of this function with alcohols. Examples are the C₁ to C₆alkyl esters or C₁ to C₆ alkylphenyl esters. Where the ester is derivedfrom compounds where B is --CH₂ OH, this term covers compounds of theformula --CH₂ OOCR' where R' is any substituted or unsubstitutedaliphatic, aromatic or aliphatic-aromatic group, particularly those of 7to 10 carbons.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids andalcohols. Here, and where ever else used, lower alkyl means having 1-6carbon atoms. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals includes the radicals of the formula --CK where K is(--OR')₂. Here, R' is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest whereacid function is concerned are the inorganic ions, sodium, potassium,calcium, and magnesium. Organic amine salts may be made with amines,particularly ammonium salts such as mono-, di- and trialkyl amines orethanol amines. Salts may also be formed with caffeine, tromethamine andsimilar molecules. Where there is a nitrogen sufficeintly basic as to becapable of forming acid addition salts, such may be formed with anyinorganic or organic acids or alkylating agent such a methyl iodide.Preferred acid addition salts are those formed with inorganic acids suchas hydrochloric acid, sulfuric acid or phosphoric acid. Any of a numberof simple organic acids having one, two or three carboxyl groups may beused for making acid addition salts.

The preferred compounds of this invention are those where the ethynylgroup and the B group are attached to the 2 and 5 positions respectivelyof a pyridine ring (the 6 and 3 positions in the nicotinic acidnomenclature being equivalent to the 2/5 designation in the pyridinenomenclature) or the 5 and 2 positions respectively of a thiophene orfuran group; n is 0, 1 or 2; and B is --COOH, an alkali metal salt ororganic amine salt, or a lower alkyl ester thereof, or --CH₂ OH and thelower alkyl esters and thereof. The more preferred compounds are:

ethyl6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate;and

6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinicacid.

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to be.administered, and similar considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral administration may also be used.

Any common topical formulation such as a solution, suspension, gel,ointment, or salve and the like may be used. Preparation of such topicalformulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or for intermuscular injection.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the drugpotentially could be used in a prophylactic manner to prevent onset of aparticular condition. A given therapeutic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, a given therapeutic concentration will bebest determined at the time and place through routine experimentation.However, it is anticipated that in the treatment of, for example, acne,or other such dermatoses, that a topical formulation containing between0.01 and 0.5 milligrams per milliliter of formulation will constitute atherapeutically effective concentration. If administered systemically,an amount between 0.01 and 1 mg per kg body weight per day will effect atherapeutic or prophylatic result in most instances.

The retinoic acid-like activity of these compounds was confirmed throughthe classic measure of retinoic acid activity involving the effect ofretinoic acid on ornithine decarboxylase. The original work on thecorrelation between retinoic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increase are unknown, it is known that12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. Thecompounds of this invention also inhibit TPA induction of ODC asdemonstrated by an assay essentially following the procedure set out inCancer Res.: 1662-1670, 1975.

SPECIFIC EMBODIMENTS

The compound of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of formula I when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by formula 1.

Compounds of formula I where the R group on the phenyl ring is hydrogenwere prepared as follows: ##STR4## Here, n is 0-5 and B is H, or aprotected acid, alcohol, aldehyde or ketone. X is Br, Cl or I butpreferrably Br or I when n is 0. I is preferred when n is 1-5.

Compounds of formula I where R is methyl were prepared as per ReactionScheme II. ##STR5##

The definitions of R is lower alkyl, n, A, B and X are the same as inScheme I.

A general description for making each of the compounds recited in theforegoing Reaction Schemes follows.

In Reaction Scheme I, The ethynyl tetrahydro naphthalene fragment ismade as follows. The 2,5-dihydroxy-2,5-dimethylhexane of formula 1 isconverted to its corresponding dichloride by treating the dihydroxycompound with hydrogen chloride gas. The reaction is effected at roomtemperature or thereabout by bubbling hydrogen chloride gas through anaqueous hydrochloric acid suspension of the dihydroxy compound until asaturated solution is obtained. The dichloride precipitates from thesolution during the process of saturation with hydrogen chloride gas.The crystalline precipitate is collected and repeatedly washed withwater and then dried, for example, under vacuum.

Compound 3, the tetramethyltetrahydronaphthalene, is prepared byreacting the 2,5-dichloro-2,5-dimethylhexane compound with benzene underFreidel-Crafts conditions. For example, the 2,5-dichloro- material isdissolved in benzene which has been cooled to between about -10° and 10°C. Approximately a 50% molar excess of anhydrous aluminum chloriderelative to the 2,5-dichloro- material is added. After addition of theanhydrous aluminum chloride, the mixture is stirred at between about 10°and 50° C., preferably at room temperature, for between 1 and 6 hours,preferably 3 hours. The solution is then refluxed for about 30 minutesto 2 hours, but preferably approximately 1 hour. The resulting solutionis acidified and the product recovered by extraction and other meanssuch as fractional distillation.

The ketone of formula 4 is obtained by treating thetetrahydronaphthalene with acetyl chloride in the presence of aluminumchloride. A suspension of the aluminum chloride in a polar inert solventis prepared under an inert atmosphere and at reduced temperature, i.e.,-10° to 10° C. The inert atmosphere may be argon or nitrogen, preferablyargon. The reaction is conveniently carried out in a solvent such asmethylene chloride. To the aluminum chloride suspension is added thetetrahydronaphthalene and acetyl chloride via a dropping funnel orsimilar device. About a 5% molar excess of acetyl chloride and 10% molarexcess of aluminum chloride, relative to the tetrahydronaphthalenematerial, is used. The reaction is effected with agitation (stirring)over 0.5-4 hours at a temperature between 10°-50° C. Preferably thereaction is effected in about 2 hours at room temperature. Then thereaction is quenched with water and/or ice, the product extracted andfurther purified by distillation or some other appropriate means.

The acetelynic function of formula 5 is introduced by means of lithiumdiisopropylamide or a similar base at reduced temperature under an inertatmosphere. The reaction is carried out in an ether-type of solvent suchas a dialkyl ether or a cyclic ether, for example, tetrahydrofuran,pyran or the like.

More specifically, lithium diisopropylamide is generated in situ bymixing diisopropylamine in a dry solvent such as tetrahydrofuran, whichis then cooled, to between -70° and -50° C. under an inert atmosphere.An equimolar amount of an alkylithium compound such as n-butyl lithiumin an appropriate solvent is then added at the reduced temperature andmixed for an appropriate time to permit formation of lithiumdiisopropylamide (LDA). The ketone of formula 4 (at least a 10% molarexcess) is dissolved in the reaction solvent, the solution cooled tothat of the LDA mixture, and added to that solution. After brief mixing,the solution is then treated with a dialkyl chlorophosphate, preferablydiethyl chlorophosphate in about a 20% molar excess. The reactionsolution is then gradually brought to room temperature. This solution isthen added to a second lithium diisopropylamide solution which isprepared in situ using dry solvent all under an inert atmosphere,preferrably argon, at reduced temperature (eg. -78° C.). Thereafter, thereaction mixture is again warmed to room temperature where it is stirredfor an extended period of time, preferably between 10 and 20 hours, mostpreferably about 15 hours. The solution is then acidified and theproduct recovered by conventional means.

Formula 6 compounds are prepared under conditions which exclude waterand oxygen. A dry, ether-type solvent such as dialkyl ether or a cyclicether such as a furan or pyran, particularly a tetrahydrofuran, may beused as the solvent. A solution of formula 5 is first prepared under aninert atmosphere such as argon or nitrogen, and then a strong base suchas n-butyl lithium is added (in about a 10% molar excess). This reactionis begun at a reduced temperature of between -10° and +10° C.,preferably about 0° C. The reaction mixture is stirred for a shortperiod, between 30 minutes and 2 hours, and then treated with about a10% molar excess of fused zinc chloride dissolved in the reactionsolvent. This mixture is stirred for an additional 1-3 hours at aboutthe starting temperature, then the temperature is increased to aboutambient temperature for 10-40 minutes.

Where a protected heteroaromatic compound is needed to couple withformula 6 compounds, such may be prepared from their correspondingacids, alcohols, ketones or aldehydes. These starting materials, theacids, alcohols aldehydes or ketones, are all available from chemicalmanufacturers or can be prepared by published methods. Acids areesterified by refluxing the acid in a solution of the appropriatealcohol in the presence of thionyl chloride or by reacting the acid andalcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. Alcohols, aldehydes and ketones all may be protected byforming, respectively, ethers and esters, acetals or ketals by knownmethods referenced below.

To increase the value of n before effecting a coupling reaction, wheresuch compounds are not available from a commercial source, theheteraromatic compounds where B is --COOH are subjected to homologationby successive treatment under Arndt-Eistert conditions. These acids arethen esterified by the general procedure outlined in the preceedingparagraph. To make formula 7, the heteroaromatic compound is dissolvedin a dry reaction solvent. The heteroaromatic compound is used in anamount approximating the molar concentration of formula 6. This solutionis introduced into a suspension of tetrakis-triphenylphosphine palladium(about a 5 to 10% molar amount relative to the reactants) in thereaction solvent at a temperature of between about -10° and +10° C. Thismixture is stirred briefly, for about 15 minutes. To this just preparedmixture is then added the pre-prepared solution of formula 6, theaddition being made at about room temperature. This solution is stirredfor an extended period, between about 15 and 25 hours at roomtemperature. The reaction is then quenched with acid and the productseparated and purified by conventional means to give the compounds offormula 7.

An alternate means for making compounds where n is 1-5 is to subject thecompounds of formula 7 where B is an acid function to homologation usingthe Arndt-Eistert method referred to above.

The acids and salts derived from formula 7 are readily obtainable fromthe corresponding esters. Basic saponification with an alkali metal basewill provide the acid. For example, an ester of Formula 7 may bedissolved in a polar solvent such as an alkanol, preferably under aninert atmosphere at room temperature, with about a three molar access ofbase, for example, potassium hydroxide. The solution is stirred for anextended period of time, between 15 and 20 hours, cooled, acidified andthe hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart. One way to prepare such compounds is to convert an acid to an acidchloride and then treat that compound with ammonium hydroxide or anappropriate amine. For example, the acid is treated with an alcoholicbase solution such as ethanolic KOH (in approximately a 10% molarexcess) at room temperature for about 30 minutes. The solvent is removedand the residue taken up in an organic solvent such as diethyl ether,treated with a dialkyl formamide and then a 10-fold excess of oxalylchloride. This is all effected at a moderately reduced temperaturebetween about -10° and +10° C. The last mentioned solution is thenstirred at the reduced temperature for 1-4 hours, preferably 2 hours.Solvent removal provides a residue which is taken up in an inertinorganic solvent such as benzene, cooled to about 0° C. and treatedwith concentrated ammonium hydroxide. The resulting mixture is stirredat a reduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation using the reagents described above.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds where B is H are prepared from the correspondinghalo-heterocyclic entity preferably where the halogen is I. Thishaloheterocyclic compound is reacted with the ethynyl zinc chlorideentity as described in Reaction Scheme I and more specifically inExample 9. Halo-substituted heterocyclic compounds where B is H arecommercially available or can be prepared by methods in the literature.Alternatively, compounds where n=1-5 and B is H, can be prepared byreducing the appropriate aldehyde or ketone using the Huang-Minlonmodification of the Wolf-Kishner reduction or a similar reaction (March,ibid, pg. 1119).

Reaction Scheme II outlines a method for making compounds of Formula Iwhere R is methyl. They are prepared under Freidel-Crafts conditionsusing 2,2,5,5-tetramethyltetrahydrofuran (formula 9) and toluene(formula 8). The furan, in a 3 to 4 molar excess, is added to toluenewhich has been cooled to between approximately -10° and 15° C. Anhydrousaluminum chloride is added in small portions with stirring in a molaramount approximating that of the toluene. When addition of the aluminumchloride is completed, the cooling bath is removed and the reactionallowed to proceed at room temperature for up to 20 hours. The solutionis then refluxed for about 1 to 3 hours, preferably about 2 hours, afterwhich the reaction is quenched by adding a dilute solution ofhydrochloric acid, preferably about 3N in concentration. The reactionproduct is extracted from the aqueous layer and further purified byappropriate means, for example, fractional distillation.

Further synthetic steps to transform compound 10 in Reaction Scheme IIto those of Formula I follows the steps and conditions outlined aboveunder the discussion of Reaction Scheme I above.

The following Examples are set out to illustrate the the invention, notto limit its scope.

EXAMPLE 1 2,5-Dichloro-2,5-dimethylhexane

Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33mol) of 2,5-dimethyl-2,5-hexanediol in 600 ml conc. hydrogen chlorideuntil the solution was saturated. The resulting crystalline product wascollected by filtration, washed repeatedly with water and dried on avacuum line to give the title compound as a crystalline white solid. PMR(CDCl₃): δ1.60 (12H, s), 1.94 (4H, s).

EXAMPLE 2 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphthalene

A vigorously stirred solution of 100 g (0.55 mol) of2,5-dichloro-2,5-dimethylhexane in 300 ml benzene was cooled in an icebath and treated with 45 g (0.34 mol) of anhydrous aluminum chloride insmall portions. This mixture was stirred at room temperature for 3hours, refluxed for 1 hour, cooled and poured into a mixture of ice andhydrogen chloride. The organic layer was recovered and the aqueous layerextracted with ether. Organic extracts were combined, washed with water,saturated Na₂ CO₃ and saturated NaCl solutions and dried (MgSO₄).

After removing the solvent, the residue was fractionally distilled (78°C., 0.8 mm) to give the title compound as a colorless liquid. PMR(CDCl₃): δ1.3(12H, s), 1.7 (4H, s), 7.1 (2H,m), 7.5 (2H,m).

EXAMPLE 3 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-6-acetylnaphthalene

A suspension of 3.45 g (25.9 mmol) aluminum chloride in 15 ml methylenechloride was cooled under argon in an ice/salt bath and treated whilestirring with a mixture of 4 g (21.2 mmol)1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene (from Example 2) and1.94 g (24.7 mmol) acetylchloride via a dropping funnel over a period of0.5 hours. Then the cooling bath was removed, the mixture stirred for 2hours at room temperature and the reaction quenched with ice. Theorganic layer was recovered and the aqueous layer extracted with 2×50 mlmethylene chloride.

The organic extracts were combined and washed with water, saturatedNaHCO₃ solution and dried (MgSO₄). solvent was removed in vacuo and theresidue kugelrohr distilled (90° C.; 0.45 mm) to give the title compoundas a colorless oil. PMR (CDCl₃): δ1.32(6H, s), 1.33 (6H, s,), 1.72(4H,s), 2.60(3H, s), 7.41(1H, d, J˜8.8 Hz), 7.71(1H, dd, J˜8.8, 2.6 Hz) 7.96(1H, d, J˜2.6 Hz)

EXAMPLE 4 1,1,4,4-Tetramethyl-6-ethynyl-1,2,3,4-tetrahydronaphthalene

To a stirred solution of 1.1572 g (11.4359 mmol) of diisopropylamine in20 ml of dry tetrahydrofuran under argon at -78° C. was added dropwisevia syringe, 7.2 ml of 1.6M (11.52 mmol) n-butyllithium in hexane. Thismixture was stirred at -78° C. for 1 hour and then treated dropwise witha solution of 2.635 g (11.4391 mmol) of1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-acetylnaphthalene in 6 ml ofdry tetrahydrofuran. After stirring at -78° C. for 1 hour, the mixturewas treated with 1.97 g (11.4175 mmol) of diethyl chlorophosphate. Thecooling bath was then removed and the mixture stirred at roomtemperature for 3.5 hours. This mixture was then transferred using adouble ended needle to a solution of lithium diisopropylamide [preparedusing 2.31 g (22.83 22 mmol) of diisopropylamine and 14.5 ml of 1.6M(23.2 mmol) n-butyllithium in hexane] in 60 ml of dry tetrahydrofuran at-78° C. Stirring was commenced at room temperature and continued for 20hours. The reaction was then quenched with 50 ml water and acidifiedwith 25 ml of 3N hydrogen chloride. Reaction product was recovered byextracting with 5×50 ml pentane. Organic extracts were combined andwashed with 3N hydrogen chloride, water, saturated NaHCO₃ and saturatedNaCl solutions and then dried (MgSO₄). Solvent was then removed andresidue purified by flash chromatography (silica, 5% ethylacetate inhexane) followed by kugelrohr distillation (60° C., 0.2 mm) to give thetitle compound as a colorless oil. PMR (CDCl₃): δ1.25 (6H, s), 1.27(6H,S), 1.66 (4H, s), 2.98 (1H, S, 7.24 (2H, s), 7.46 (1H, s).

EXAMPLE 5 1,1,4,4,6-Pentamethyl-1,2,3,4-tetrahydronaphthalene

To a cooled (0° C.) mixture of 40 g (0.4341 mol) toluene and 25 g (0.195mol) 2,2,5,5-tetramethyl tetrahydrofuran was added in small portionswith stirring 26.6 g (0.2 mol) of anhydrous aluminum chloride. Thecooling bath was removed and mixture stirred at room temperature for 20hours and then heated at reflux for 2 hours. The reaction mixture wascooled to room temperature and then quenched by adding a mixture of iceand 100 ml 3N hydrogen chloride. The organic layer was separated and theaqueous layer extracted with 3×75 ml ether. Organic extracts werecombined and washed with 3N hydrogen chloride, saturated NaHCO₃ andsaturated NaCl solutions and dried (MgSO₄). Solvent was removed in vacuoand the residue fractionally distilled to give the title compound as acolorless oil. PMR (CDCl₃): 1.30 (6H, S), 1.32 (6H, S), 1.70 (4H, S),2.33 (3H, S), 6.98 (1H, d, J˜7 Hz), 7.14 (1H, S), 7.23 (1H, d, J˜7 Hz).

Proceeding in a similar manner, but substuting for toluene theappropriate alkylphenyl moiety, there may be prepared the followingcompounds:

1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene;

1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphthalene;

1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphthalene; and

1,1,4,4-tetramethyl-6-pentyl-1,2,3,4-tetrahydronaphthalene.

EXAMPLE 6 1,1,4,4,7-Pentamethyl-6-acetyl-1,2,3,4-tetrahydronaphthalene

To a suspension of 13.72 g (102.9 mmol) aluminum chloride in 40 mldichloroethane, which was cooled in an ice-acetone bath under argon, wasadded with stirring over a 1 hour period a solution of 17.11 g (84.56mmol) of the 1,1,4,4,6-Pentamethyl-1,2,3,4-tetrahydronapthalene (fromExample 5) in 10 ml dichloroethane. The cooling bath was removed and themixture stirred at room temperature for 3 hours and then poured ontoice. The organic layer was separated and the aqueous layer extractedwith 3×75 ml methylene chloride. The organic layers were combined andwashed several times with water, then saturated NaHCO₃ and saturatedNaCl solutions and then dried (MgSO₄). Solvent was removed in vacuo andthe residue subjected to Kugelrohr distillation (70° C., 0.15 mm) togive the title compound as a low-melting yellow solid. PMR (CDCl₃):δ1.30 (6H, s), 1.32 (6H, s), 1.70 (4H, s), 2.51 (3H, s), 2.59 (3H, s),7.16 (1H, s), 7.69 (1H, s)

Likewise, the compounds prepared as per Example 5 are converted to thecorresponding acetyl form.

EXAMPLE 7 1,1,4,4,7-Pentamethyl-1,2,3,4-tetrahydronaphthalene

To a stirred solution of 794.2 mg (7.8486 mmol) diisopropylamine in 7 mldry tetrahydrofuran under argon at -78° C. was added dropwise 4.9 ml of1.6M (7.84 mmol) n-butyllithium in hexane. This solution was stirred at-78° C. for 1.25 hours and then treated via a double ended needle with asolution of 1.9 g (7.7749 mmol) of1,1,4,4,7-pentamethyl-6-acetyl-1,2,3,4-tetrahydronapthalene in 4 ml drytetrahydrofuran. After stirring at -78° C. for 1 hour, the mixture wastreated with 1.3134 g (7.6117 mmol) of diethyl chlorophosphate. Thecooling bath was removed and mixture stirred at room temperature for 3hours. This material was then transferred using a double ended needleinto a solution of lithium diisopropylamide [prepared as above using1.5884 g (15.6972 mmol) of diisopropylamine and 10 ml of 1.6M (16 mmol)n-butyllithium in hexane] in 15 ml dry tetrahydrofuran at -78° C. Thecooling bath was removed and mixture stirred at room temperature for 15hours, then quenched with 50 ml water, and acidified to pH 1 with 3Nhydrogen chloride. The mixture was extracted with 3×75 ml petroleumether and the organic extracts were combined, washed with saturatedNaHCO₃ and saturated NaCl solutions and dried (MgSO₄). Solvent was thenremoved in vacuo and the residue purified by flash chromatography(silica; 3% ethyl acetate in hexane) followed by kugelrohr distillation(50° C., 0.05 mm) to give the title compound as a colorless oil. PMR(CDCl₃): δ1.28 (12H, s), 1.67 (4H, s), 1.42 (3H, s), 3.20 (1H, s), 7.15(1H, s), 7.44 (1H, s).

In a similar manner, the 6-position alkyl analogues from Example 6 areconverted to their corresponding ethynyl derivative exemplified by thefollowing compounds:

1,1,4,4-tetramethyl-6-ethyl-7-ethynyl-1,2,3,4-tetrahydronapthalene;

1,1,4,4-tetramethyl-6-propyl-7-ethynyl-1,2,3,4-tetrahydronaphthalene;

1,1,4,4-tetramethyl-6-butyl-7-ethynyl-1,2,3,4-tetrahydronaphthalene; and

1,1,4,4-tetramethyl-6-pentyl-7-ethynyl-1,2,3,4-tetrahydronaphthalene.

EXAMPLE 8 Ethyl 6-chloronicotinoate

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g (0.03 mol)dimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand residue subjected to flash chromatography to give the title compoundas a low-melting white solid. PMR (CDCl₃): δ1.44 (3H, t, J˜6.2 Hz) 4.44(2H, q, J˜6.2 Hz), 7.44 (1H, d, J˜8.1 Hz), 8.27 (1H, dd, J˜8.1 Hz, 3Hz), 9.02 (1H, d, J3 Hz).

This procedure may be used to esterify any of the other halo-substitutedacids employed in the making of these compounds such as

ethyl-2-(2-chloropyrid-5-yl)acetate;

ethyl-5-(2-chloropyrid-5-yl)pentanoate;

ethyl-2-(2-iodofur-5-yl)acetate;

ethyl-5-(2-iodofur-5-yl)pentanoate;

ethyl-2-(2-iodothien-5-yl)acetate;

ethyl-5-(2-iodothien-5-yl)pentanoate;

ethyl-5-(3-chloropyridazin-6-yl)acetate; and

ethyl-5-(3-chloropyridazin-6-yl)pentanoate.

EXAMPLE 9 Ethyl6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate

The reaction vessels used in this procedure were flame dried undervacuum and all operations were carried out in an oxygen-free argon ornitrogen atmosphere. To a solution of 417.6 mg (1.9667 mmol) of1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-ethynylnapthalene in 3 ml ofdry tetrahydrofuron (THF) at 0° C. was added dropwise 1.3 ml of 1.6M(2.32 mmol) n-butyllithium in hexane. This mixture was stirred at 0° C.for 10 minutes and at room temperature for 15 minutes, cooled again to0° C. and then treated by double-ended needle with a solution of 290 mg(2.1279 mmol) of fused zinc chloride in 4 ml dry THF. The mixture wasstirred at 0° C. for 45 minutes and at room temperature for 15 minutes.A solution of 361.1 mg (1.9455 mmol) of ethyl 6-chloronicotinoate in 4ml dry THF was transferred by double ended needle into a suspension of420 mg (0.3635 mmol) of tetrakistriphenylphosphine palladium in 4 ml dryTHF, the resultant mixture stirred at room temperature for 15 minutesand then treated by double ended needle with the solution of alkynylzinc prepared above. The reaction mixture was stirred at roomtemperature for 70 hours and then quenched with ice and 30 ml of 3N HCl.The resultant mixture was extracted with 3×50 ml of ether, the etherextracts combined and washed successively with saturated NaHCO₃ andsaturated NaCl solutions and then dried (MgSO₄). The ether solution wasfiltered and concentrated in-vacuo. The resultant crude product waspurified by flash chromatography (silica, 10% ethyl acetate in hexanes)followed by recrystallization from a mixture of ethylacetate in hexaneto give the title compound as a pale cream solid.

PMR (CDCl₃): δ1.28 (6H, s), 1.30 (6H, s), 1.43 (3H, t, J˜7.1 Hz), 1.69(4H, s), 4.42 (2H, q, J˜7.1 Hz), 7.31 (1H, d, J˜8.3 Hz), 7.38 (1H, d,J˜8.3 Hz), 7.59 (1H, d, J˜8.3 Hz), 7.60 (1H, s), 8.28 (1H, dd, J˜8.3 Hz,2.5 Hz), 9.20 (1H, d, J˜2.5 Hz).

Proceeding in a similar manner, but substituting1,1,4,4,6-pentamethyl-6-ethynyl-1,2,3,4-tetrahydronaphthalene fromExample 7 or another compound prepared as per that Example for the1,1,4,4-tetramethyl compound of the preceding paragraph and, ifappropriate, a suitable halogen-substituted heterocycle for ethyl6-chloronicotinoate, there can be prepared the following compounds:

ethyl6-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate;

ethyl6-[2-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate;

ethyl6-[2-(3-pentyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate;

ethyl[2((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrid-5-yl]acetate;

ethyl3-[2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrid-5-yl]propionate;

ethyl5-[2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)fur-2-yl]acetate;

ethyl3-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)fur-2-yl]propionate;

ethyl5-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)fur-2-yl]pentanoate;

ethyl[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)thien-2-yl]acetate;

ethyl3-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)thien-2-yl]propionate;

ethyl 5-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)thien-2-yl]pentanoate;

ethyl[6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl3-[6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridazin-3-yl]propionate;

ethyl5-[6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl3-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-yl]propionate;

ethyl5-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl [2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-5-yl]acetate;

ethyl3-[2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-5-yl]propionate;

ethyl5-[2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-5-yl]pentanoate;

ethyl [5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl3-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-yl]propionate;and

ethyl5-[5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-yl]pentanoate.

EXAMPLE 106-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinicacid

Absolute ethanol was degassed by applying a vacuum while simultaneouslybubbling nitrogen through it. A solution of 188 mg (0.5201 mmol) ethyl6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoatein 2 ml absolute ethanol was treated with 800 ml of a 1.65M (1.32 mmol)solution of potassium hydroxide in ethanol and water. The mixture wasstirred at room temperature for 18 hours and then the solvent removed invacuo. The residue was dissolved in water and extracted with 50 mlether, which was discarded. The aqueous layer was then acidified withglacial acetic acid and extracted with 4×50 ml ether. The ether extractswere combined, washed with water, saturated NaCl solution and then dried(MgSO₄). Solvent was removed in vacuo to give the title compound as apale yellow solid. PMR (CDCl₃): δ1.31 (12H, s), 1.71(4H, s), 7.34 (1H,d, J˜7.8 Hz), 7.40 (1H, d, J˜7.8 Hz), 7.62 (1H, s), 8.39 (1H, dd, J˜7.3Hz, 2.1 Hz), 9.33 (1H, d, J˜2.1 Hz).

In the same manner, any of the esters prepared in Example 9 may beconverted to their corresponding acid.

EXAMPLE 112-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine

A 250 ml 3-necked flask is fitted with a stirrer, a dropping funnel, anitrogen inlet and a thermometer. In the flask is placed a solution of379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethylether. The solution is cooled to -65° C. under nitrogen and a solutionof 3.6148 g (10 mmol) of ethyl6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoatein 15 ml of dry ether is added dropwise at a rate such that thetemperature does not exceed -60° C. The mixture is stirred at -30° C.for 1 hour and the excess hydride is then destroyed by the addition of300 mg (3.4 mmol) of ethyl acetate. The reaction mixture is thenhydrolyzed by adding 3 ml of saturated ammonium chloride solution andallowing the temperature to rise to room temperature. The mixture isthen filtered and the residue washed with ether. The ether layer is thenwashed with saturated sodium chloride solution, dried (MgSO₄) and thenconcentrated in vacuo. The residue is purified by chromatographyfollowed by recrystalliztion to give the title compound.

EXAMPLE 122-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-acetoxymethylpyridine

A solution of 3.195 g (10 mmol) of2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine,600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) ofdicyclohexylcarbodiimide and 460 mg (3.765 mmol) of4-dimethylaminopyridine in 150 ml methylene chloride is stirred at roomtemperature for 48 hours. The reaction mixture is then filtered and theresidue washed with 50 ml of methylene chloride. The filtrate is thenconcentrated in vacuo and the residue is purified by chromatographyfollowed by recrystallation to give the title compound.

By the same process, any acid or ester of this invention may beconverted to its corresponding primary alcohol analog.

EXAMPLE 132-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-pyridine-5-carboxaldehyde

A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in25 ml of methylene chloride is placed in a 4-necked flask equipped witha stirrer, a thermometer and two pressure-equalizing addition funnelsfitted with drying tubes. The solution is cooled to -60° C. and thentreated dropwise with a solution of 1.875 g (24 mmol) of dimethylsulfoxide (distilled from calcium hydride) in 5 ml of methylene chlorideover a five minute period. The reaction mixture is then stirred at -60°C. for an additional 10 minutes. A solution of 3.195 g (10 mmol) of2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridinein 10 ml of methylene chloride is then added to the reaction mixtureover a period of 5 minutes. The mixture is stirred for a further 15minutes and is then treated with 5.06 g (50 mmol) of triethylamine. Thecooling bath is then removed and the mixture is allowed to warm to roomtemperature. Thirty ml of water is then added to the mixture andstirring is continued for a further 10 mintues. The organic layer isthen separated and the aqueous layer is extracted with 20 ml ofmethylene chloride. The organic layers are then combined and washedsuccessively with dilute HCl, water and dilute Na₂ CO₃ solution and thendried (MgSO₄). The solution is then filtered and concentrated in vacuoand the residue is purified by chromatography followed byrecrystallization to give the title compound.

All alcohols of this invention may be oxidized to their correspondingaldehyde by this method.

EXAMPLE 142-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-(1-hydroxypropyl)pyridine

Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether isplaced in a 3-necked flask fitted with a mechanical stirrer, a refluxcondenser protected by a drying tube and a pressure-equalizing droppingfunnel protected by a drying tube. The flask is cooled in an ice-bathand a solution of 3.174 g (10 mmol) of2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]pyridine-5-carboxaldehyde in 10 ml of dry ether is added slowly withvigorous stirring. The cooling bath is then removed and the mixtureheated at reflux for 3 hours. The mixture is then cooled in an ice-saltbath and 5 ml of saturated ammonium chloride solution is added. Themixture is stirred for a further 1 hour and then filtered and theresidue washed with two 10 ml portions of ether. The ether solution isthen separated, dried (MgSO₄) and the ether removed in vacuo. Theresidue is then purified by chromatography followed by recrystallizationto give the title compound.

Using the same procedure, but substituting for the pyridine compoundnoted above, any of the other heteroaromatic aldehydes of this inventioncan be converted to a secondary alcohol.

Such secondary alcohols may be converted to their corresponding ketoneusing the same reagents in approximately the same relative amounts ofreagent to reactant and essentially the same conditions described inExample 13.

EXAMPLE 152-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-dimethoxymethylpyridine

A round-bottomed flask is fitted with a Dean-Stark apparatus under areflux condenser protected by a drying tube. A mixture of 3.174 g (12mmol) of2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]pyridine-5-carboxaldehyde,4.80 mg (15 mmol) of anhydrous methanol, 2 mg of p-toluenesulfonic acidmonohydrate and 10 ml of anhydrous benzene is placed in the flask andthe mixture heated at reflux under nitrogen until close to thetheoretical amount of water is collected in the Dean-Stark trap. Thereaction mixture is cooled to room temperature and washed successivelywith 5 ml of 10% sodium hydroxide solution and two 5 ml portions ofwater and then dried (MgSO₄). The solution is then filtered and thesolvent removed in vacuo. The residue is purified by chromatography andthen recrystalliztion to give the title compound.

In a similar manner, any aldehyde or ketone of any compound of thisinvention may be converted to an acetal or a ketal.

EXAMPLE 16

Preferably, these compounds may be administered topically using variousformulations. Such formulation may be as follows.

    ______________________________________                                        Ingredient         Weight/Percent                                             ______________________________________                                        Solution                                                                      Retinoid           0.1                                                        BHT                0.1                                                        Alcohol USP        58.0                                                       Polyethylene Glycol 400 NF                                                                       41.8                                                       Gel                                                                           Retinoid           0.1                                                        BHT                0.1                                                        Alcohol USP        97.8                                                       Hydroxypropyl Cellulose                                                                          2.0                                                        ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR6## where R ishydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl, or pyrazinyl; nis 0-5; and B is H, --COOH or a pharmaceutically acceptable salt, orester of saturated aliphatic alcohols of ten or fewer carbon atoms, orthe cyclic or saturated aliphatic cyclic alcohols of 5 to 10 carbonatoms, or phenol, or amide or mono- or disubstituted amide of saturatedaliphatic amines of 10 or fewer carbon atoms, or the cyclic or saturatedaliphatic cyclic radicals of 5 to 10 carbon atoms thereof, --CH₂ OH or alower alkyl ether or ester of saturated aliphatic acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic acids of 5 to10 carbon atoms, or benzoic acid thereof, or --CHO or a lower alkylacetal derivative thereof, or --COR₁ or a lower alkyl ketal derivativethereof where R₁ is (CH₂)_(m) CH₃ where m is 0-4; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 where R is hydrogenor methyl, n is 0, 1 or
 2. 3. The compound of claim 2 where B is --COOHor a pharmaceutically acceptable salt, ester or amide thereof.
 4. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of the formula ##STR7## where R is hydrogen orlower alkyl; A is pyridazinyl, pyrimidinyl, or pyrazinyl; n is 0-5; andB is H, --COOH or a pharmaceutically acceptable salt, or ester ofsaturated aliphatic alcohols of ten or fewer carbon atoms, or the cyclicor saturated aliphatic cyclic alcohols of 5 to 10 carbon atoms, orphenol, or amide or mono- or disubstituted amide of saturated aliphaticamines of 10 or fewer carbon atoms, or the cyclic or saturated aliphaticcyclic radicals of 5 to 10 carbon atoms thereof, --CH₂ OH or a loweralkyl ether or ester of saturated aliphatic acids of ten or fewer carbonatoms or the cyclic or saturated aliphatic cyclic acids of 5 to 10carbon atoms or benzoic acid thereof, or --CHO or a lower alkyl acetalderivative thereof, or --COR₁ or a lower alkyl ketal derivative thereofwhere R₁ is (CH₂)_(m) CH₃ where m is 0-4; or a pharmaceuticallyacceptable salt thereof.
 5. A composition according to claim 4 havinganti-psoriatic activity in a mammal.
 6. A method of treating psoriasisin a mammal which method comprises administering alone or in conjunctionwith a pharmaceutically acceptable excipient, a therapeuticallyeffective amount of a compound of the formula ##STR8## where R ishydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl, or pyrazinyl; nis 0-5; and B is H, --COOH or a pharmaceutically acceptable salt, orester of saturated aliphatic alcohols of ten or fewer carbon atoms, orthe cyclic or saturated aliphatic cyclic alcohols of 5 to 10 carbonatoms, or phenol, or amide or mono- or disubstituted amide of saturatedaliphatic amines of 10 or fewer carbon atoms, or the cyclic or saturatedaliphatic cyclic radicals of 5 to 10 carbon atoms thereof, --CH₂ OH or alower alkyl ether or ester of saturated aliphatic acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic acids of 5 to10 carbon atoms, or benzoic acid thereof, or --CHO or a lower alkylacetal derivative thereof, or --COR₁ or a lower alkyl ketal derivativethereof where R₁ is (CH₂)_(m) CH₃ where m is 0-4; or a pharmaceuticallyacceptable salt thereof.